bioRxiv : the preprint server for biology最新文献

Background: Reduced empathy is a hallmark of individuals with high psychopathy, who are overrepresented among incarcerated men. However, a comprehensive mapping of cortical structure in relation to empathy and psychopathy is lacking.

Methods: In 804 incarcerated adult men, we administered the Perspective Taking (IRI-PT) and Empathic Concern (IRI-EC) subscales of the Interpersonal Reactivity Index, Hare Psychopathy Checklist-Revised (PCL-R; Interpersonal/Affective [F1] and Lifestyle/Antisocial [F2] factors), and T1-weighted MRI to quantify cortical thickness (CT) and surface area (SA). We also included the male sample from the Human Connectome Project (HCP; N = 501) to probe the replicability of structural-covariance gradients.

Results: PCL-R F1 was uniquely negatively related to IRI-EC, while PCL-R F2 was uniquely negatively related to IRI-PT. Cortical structure was not related to either IRI subscale, although there was effect-size differentiation by cytoarchitectonic class and/or functional network. CT was related to PCL-R F1 (mostly positively), SA was related to both PCL-R factors (only positively), and both cortical indices demonstrated out-of-sample predictive utility for PCL-R F1. The high-psychopathy group (N = 178) scored uniquely lower on IRI-EC while having increased SA (but not CT); across the cortex, effect sizes were largest in the paralimbic class and somatomotor network, and meta-analytic task-based activations corroborated affective/sensory importance. Finally, the total sample revealed anterior-posterior gradients of covariance, which were replicated in the HCP sample. In the high-psychopathy group, the gradient of CT (but not SA) was globally compressed.

Conclusions: Most notably, high-psychopathy men had reduced empathic concern, increased SA, and compressed macroscale organization of CT.

Traction force and mechanosensing (the ability to sense the mechanical attributes of the environment) are two key factors that enable a cell to modify its behavior during migration. Previously, it was determined that the calpain small subunit, calpain 4 (CapnS1), regulates the production of traction force independent of its proteolytic holoenzyme. A proteolytic enzyme is formed by calpain 4 binding to either of its catalytic partners, calpain 1 and 2. To further understand how calpain 4 regulates traction force, we used two-hybrid analysis to identify more components of the traction pathway. We discovered that basigin, an integral membrane protein and a documented inducer of matrix-metalloprotease (MMP), binds to calpain 4 in two-hybrid and pull-down assays. Traction force was deficient when basigin was silenced in MEF cells, and this deficiency was also reflected in the defect in substrate adhesion strength. Unlike Capn4 ^-/- MEF cells, the cells deficient in basigin had normal mechanosensing abilities. Together, these results implicate basigin in the pathway in which calpain 4 regulates traction force independent of the catalytic large subunits.

Tumor cell lines with elevated chromosome numbers frequently exhibit elevated expression of Mps1. These tumors are also dependent on high Mps1 activity for their survival. Mps1 is a conserved kinase involved in controlling aspects of chromosome segregation in mitosis and meiosis. The mechanistic explanation for the Mps1-addiction of aneuploid cells is unknown. To address this question, we explored Mps1-dependence in yeast cells with increased sets of chromosomes. These experiments revealed that in yeast, increasing ploidy leads to delays and failures in orienting chromosomes on the mitotic spindle. Yeast cells with elevated numbers of chromosomes proved vulnerable to reductions of Mps1 activity. Cells with reduced Mps1 activity exhibit an extended prometaphase with longer spindles and delays in orienting the chromosomes. One known role of Mps1 is in recruiting Bub1 to the kinetochore in meiosis. We found that the Mps1-addiction of polyploid yeast cells is due in part to its role in Bub1 recruitment. Together, the experiments presented here demonstrate that increased ploidy renders cells more dependent on Mps1 for orienting chromosomes on the spindle. The phenomenon described here may be relevant in understanding why high-ploidy cancer cells exhibit elevated reliance on Mps1 expression for successful chromosome segregation.

Phenotypic correlations between complex human traits have long been observed based on epidemiological studies. However, the genetic basis and underlying mechanisms are largely unknown. Here we developed a gene-based approach to measure genetic overlap between a pair of traits and to delineate the shared genes/pathways, through three steps: 1) translating SNP-phenotype association profile to gene-phenotype association profile by integrating GWAS with eQTL data using a newly developed algorithm called Sherlock-II; 2) measuring the genetic overlap between a pair of traits by a normalized distance and the associated p value between the two gene-phenotype association profiles; 3) delineating genes/pathways involved. Application of this approach to a set of GWAS data covering 59 human traits detected significant overlap between many known and unexpected pairs of traits; a significant fraction of them are not detectable by SNP based genetic similarity measures. Examples include Cancer and Alzheimer's Disease (AD), Rheumatoid Arthritis and Crohn's disease, and Longevity and Fasting glucose. Functional analysis revealed specific genes/pathways shared by these pairs. For example, Cancer and AD are co-associated with genes involved in hypoxia response and P53/apoptosis pathways, suggesting specific mechanisms underlying the inverse correlation between them. Our approach can detect yet unknown relationships between complex traits and generate mechanistic hypotheses and has the potential to improve diagnosis and treatment by transferring knowledge from one disease to another.

Self-organized criticality is a hallmark of complex dynamic systems at phase transitions. Systems that operate at or near criticality have large-scale fluctuations or "avalanches", the frequency and duration power of which are best fit with a power law revealing them to be scale-free and fractal, and such power laws are ubiquitous. It is an attractive concept in neuroscience since spiking avalanches are exhibited by neural tissue, and may underpin how minuscule events could scale up to circuits and provide adaptive psychobiological function. Much is yet to be understood about criticality in vivo in the healthy brain and in disorders such as addiction, as drugs may alter the critical state's "tuning" to generate drug seeking and dysphoria. Thus, here a novel toolset was developed to use neural avalanches and their self-similarity, rather than power law fit slope exponents as is canonically done, to quantify criticality in a previously collected high-density electrophysiological in vivo corticostriatal dataset from a mouse model of early cocaine abstinence. During behavioral quiescence, in the prefrontal cortex but not ventral striatum of cocaine-dosed mice, it was found that critical tuning is enhanced compared to drug-free controls. Additionally, an empirical biological demonstration of complexity's theoretical correlation to criticality was shown in drug-free mice, was exponentially enhanced in drug-treated cortex, but was absent in the drug-treated striatum. As shown, quantifying criticality grants experimental support for the "critical brain hypothesis" and allows for statistical interpretation of inter-subject variability and development of further testable hypotheses in systems neuroscience.

Significance statement: The "critical brain hypothesis" asserts neural networks are comparable to material in phase transitions at a critical point, their "avalanches" of system-wide spike bursts best seen in log-log plots of probability vs. avalanche size or duration, with slope following a scale-free or fractal power law. In discussing criticality, "critical tuning" is mentioned but quantification thereof left for later experimentation, despite being necessary for a scientific hypothesis. Presented are methods to quantify critical tuning through assessing similarity or fractalness among corticostriatal avalanches collected using high-density electrophysiology in cocaine-conditioned mice, along with an empirical in vivo confirmation of the mathematical concept that data complexity correlates with criticality. Interestingly, cocaine enhances critical tuning in cortex and aberrantly modifies complexity in a region-specific manner.

Measuring ongoing cellular activity is essential to understanding the dynamic functions of biological organisms. The most popular current approach is imaging fluorescence-based genetically encoded Ca²⁺ indicators (GECIs). While fluorescent probes are useful in many contexts, bioluminescence-based GECIs-probes that generate light through oxidation of a small-molecule by a luciferase or photoprotein-have several distinct advantages. Because bioluminescent (BL) GECIs do not use the bright extrinsic excitation light required for fluorescence, BL GECIs do not photobleach, do not suffer from nonspecific autofluorescent background, and do not cause phototoxicity. Further, BL GECIs can be applied in contexts where directly shining photons on an imaging target is not possible. Despite these advantages, the use of BL GECIs has to date been limited by their small changes in bioluminescence intensity, high baseline signal at resting Ca²⁺ concentrations, and suboptimal Ca²⁺ affinities. Here, we describe a new BL GECI, CaBLAM (Ca²⁺ BioLuminescence Activity Monitor), that displays much higher dynamic range than previous BL GECIs and has a Ca²⁺ affinity suitable for capturing physiological changes in cytosolic Ca²⁺ concentration. With these improvements, CaBLAM captures single-cell and subcellular resolution activity at high frame rates in cultured neurons and in vivo, and allows multi-hour recordings in mice and behaving zebrafish. This new advance provides a robust alternative to traditional fluorescent GECIs that can enable or enhance imaging across many experimental conditions.

Bacterial species often undergo rampant recombination yet maintain cohesive genomic identity. Ecological differences can generate recombination barriers between species and sustain genomic clusters in the short term. But can these forces prevent genomic mixing during long-term coevolution? Cyanobacteria in Yellowstone hot springs comprise several diverse species that have coevolved for hundreds of thousands of years, providing a rare natural experiment. By analyzing more than 300 single-cell genomes, we show that despite each species forming a distinct genomic cluster, much of the diversity within species is the result of hybridization driven by selection, which has mixed their ancestral genotypes. This widespread mixing is contrary to the prevailing view that ecological barriers can maintain cohesive bacterial species and highlights the importance of hybridization as a source of genomic diversity.

Lymphatic transport facilitates the presentation of cancer antigens in tumor-draining lymph nodes (tdLNs), leading to T cell activation and the generation of systemic anti-cancer immune surveillance. Surgical removal of tdLNs to control cancer progression is routine in clinical practice. However, whether removing tdLNs impairs immune checkpoint blockade (ICB) is still controversial. Our analysis demonstrates that melanoma patients remain responsive to PD-1 checkpoint blockade after regional LN dissection. We were able to recapitulate the persistent response to ICB after regional LN resection in murine melanoma and mammary carcinoma models. Mechanistically, soluble antigen is diverted to distant LNs after tdLN dissection. Consistently, robust ICB responses in patients with head and neck cancer after primary tumor and tdLN resection correlated with the presence of reactive LNs in distant sites. These findings indicate that distant LNs sufficiently compensate for the removal of direct tdLNs and sustain the response to ICB.

Many species regenerate lost body parts following amputation. Most limb regeneration research has focused on the immediate injury site. Meanwhile, body-wide injury responses remain largely unexplored but may be critical for regeneration. Here, we discovered a role for the sympathetic nervous system in stimulating a body-wide stem cell activation response to amputation that drives enhanced limb regeneration in axolotls. This response is mediated by adrenergic signaling, which coordinates distant cellular activation responses via the α_2A-adrenergic receptor, and local regeneration responses via β-adrenergic receptors. Both α_2A- and β-adrenergic signaling act upstream of mTOR signaling. Notably, systemically-activated axolotls regenerate limbs faster than naïve animals, suggesting a potential selective advantage in environments where injury from cannibalism or predation is common. This work challenges the predominant view that cellular responses underlying regeneration are confined to the injury site and argues instead for body-wide cellular priming as a foundational step that enables localized tissue regrowth.

Melanoma plasticity, driven by phenotype state switching, underlies clinically relevant traits such as metastasis and therapy resistance. As melanoma progression is thought to recapitulate aspects of neural crest cell (NCC) development, understanding embryonic melanocyte specification and lineage fate decisions of closely related NCCs may illuminate the pathways co-opted during disease evolution. Here, we use a mouse model to isolate and sequence Dopachrome tautomerase (Dct) expressing NCCs, the precursors of melanocytes, at two key developmental stages. We classify these lineages and devise a Developmental Gene Module (DGM) scoring system to interrogate lineage state switching in melanoma samples. In bulk transcriptomes, activation of DGMs representing embryonic Schwann Cell Precursors (SCPs)-multipotent stem cells-in patient tumors predicts poor response to immune checkpoint inhibitors (ICI). Co-activation of SCP and Mesenchymal-like (Mes.) modules further correlates with resistance to MAPK inhibitors. Notably, single-cell analyses reveal that melanoma cells can simultaneously express multiple DGMs, forming "hybrid" states. Cells in a hybrid Neural/SCP state are enriched in early metastasis and ICI-resistant tumors and are insensitive to inflammatory stimuli. We demonstrate that targeting Hdac2, a histone deacetylase associated with this Neural/SCP hybrid state, promotes a mesenchymal-like state switch, remodels the tumor microenvironment, and sensitizes melanoma cells to TNFα and tumors to ICI therapy. Our methodology thus reveals dynamic patterns of lineage state switching correlated with melanoma tumor evolution to drive insight into new therapeutic targets.